Approximately 25-30% of breast cancer patients overexpress the proto-oncoprotein and cell surface receptor c-erbB2 (human epidermal growth factor receptor 2 protein), also known as HER2/neu. Overexpression of the c-erbB2 oncogene has been linked to poor outcome and decreased survival for patients. The HER-2/neu protooncogene is overexpressed in 20-30% of metastatic breast cancers, and is associated with decreased survival and increased recurrence of breast cancer. HER-2/neu is also overexpressed in other cancer types including endometrial cancer, kidney cancer, gastric cancer, and prostate cancer. Presently, the most common form of treatment for these patients is the use of the humanized monoclonal antibody Trastuzumab, also known as Herceptin®.
Herceptin® is a recombinant DNA-derived humanized monoclonal antibody that selectively binds with high affinity (Kd=5 nM) to the extracellular domain of c-erbB2 in a cell-based assay. See Science 1985; 230:1132-9 and Cancer Res 1993; 53:4960-70. Herceptin® is an IgG1 kappa antibody that binds to HER2 and contains human framework regions with the complementarity-determining regions of a murine antibody (4D5). Id. However, only 25% of the patients treated with Herceptin® or any other antibody to c-erbB2/HER2 are responsive to this therapy. Several models have been postulated to explain resistance to treatment with c-erbB2/HER2 antibodies. What is needed are compositions and methods for restoring sensitivity to treatment with HER2/neu antagonists.